One important aspect of motivation that is compromised in psychiatric/neurological diseases is the ability to overcome effort related obstacles to obtain a valued outcome. Dopaminergic modulation of striatal outputs is crucial to this type of reward motivated behavior. Adenosine A2A receptors, which are coexpressed with dopamine D2 receptors on the same population of striatal neurons, modulate effort related choice by means of a reciprocal antagonistic relationship with D2 receptors. The research in this proposal will use a trangenic mouse model which selectively and reversibly overexpresses the D2 receptor in the striatum (D2OE) to assess the efficacy of targeting A2A receptors for treatment of the motivational deficits associated with schizophrenia. The D2OE mouse models some of the core motivational impairments displayed by patients with schizophrenia, including deficits in a concurrent lever pressing/free feeding task that measures aspects of motivation and effort related choice. In addition, preliminary assessment of brain changes that result from striatal D2 overexpression indicate that the adenosine A2A receptor is significantly downregulated in the D2OE mice. The proposed research will use a combination of behavioral, genetic, and pharmacological approaches to characterize the role of the adenosine A2A receptor in modulating effort related choice in D2OE mice. First, we will more fully characterize the effort related choice phenotype in D2OE mice and see if the deficit is modulated by the work requirement. We will verify downregulation of A2A expression, and determine whether A2A expression can be rescued by turning off the transgene in the adult mouse. We will assess whether the effort related choice phenotype can be rescued by acute and chronic antagonism of D2 receptors. We will also assess the efficacy of A2A agonism as a treatment for the effort related choice phenotype. Finally, we will assess changes in D2 receptors as a function of chronic A2A agonism. PUBLIC HEALTH RELEVANCE: Current treatments for schizophrenia are not successful in treating the motivational deficit. The present research will help to clarify the neural circuits underlying reward motivated behavior, and may suggest therapeutic strategies for treating the motivational deficits in schizophrenia and other psychiatric/neurological diseases.